Pyridine analogs as C5A antagonists

ABSTRACT

The present invention provides novel compounds of Formula I which are antagonists of the C5a receptor. Compounds of the present invention are useful for the treatment of various C5a-mediated diseases and disorders; accordingly the present invention provides a method for the treatment of C5a-mediated diseases using the novel compounds described herein, as well as pharmaceutical compositions containing them.

BACKGROUND OF THE INVENTION

The complement system is a key component of innate immunity. It is foundin the blood of mammals and is composed of over 25 proteins thatrecognize antibodies (immune complexes) and various pathogen surfaceswhich trigger a cascade of events aimed at protecting the host from“foreign” treats. During the complement activation cascade, a smallpeptide of 74 amino acids named C5a, is produced. This peptide has anumber of biological activities including: 1) increases the permeabilityof small blood vessels, 2) induces the contraction of smooth muscles, 3)attracts and stimulates the pro-inflammatory activity of a variety ofimmune cells like macrophages, neutrophils and mast cells (reviewed byKohl in Molecular Immunology (2001), 38:175-187). C5a mediates theseeffects through a G-protein coupled receptor named C5aR.

Excessive or uncontrolled complement activation can sometimes injure thehost. The production of C5a is implicated in the pathogenesis of avariety of inflammatory conditions such as rheumatoid arthritis,systemic lupus erythematosus, glomerulonephritis, ischemic heartdiseases, reperfusion injury, sepsis, psoriasis, atherosclerosis,inflammatory bowel diseases (IBD), adult respiratory distress syndrome(ARDS), asthma, COPD and Alzheimer's disease (reviewed by Mizuno andMorgan in Curr Drug Targets Inflamm Allergy (2004) 3:87-96 and by Kohlin Molecular Immunology (2001), 38:175-187).

Agents blocking the interaction of C5a with its receptor would be usefulfor treating the various inflammatory disorders driven by complementactivation.

SUMMARY OF THE INVENTION

The present invention provides novel compounds of Formula I which areantagonists of the C5a receptor. Compounds of the present invention areuseful for the treatment of various C5a-mediated diseases and disorders;accordingly the present invention provides a method for the treatment ofC5a-mediated diseases using the novel compounds described herein, aswell as pharmaceutical compositions containing them.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect this application is directed to compounds of Formula I

or a pharmaceutically acceptable salts thereof, or when only one of W,X, Y and Z is —N—, the N-oxide thereof, wherein:W, X, Y and Z are each independently selected from —CH— and —N,provided that at least one, but not more than two of W, X, Y and Z are—N—, and still further provided that when two of W, X, Y and Z are —N—,then R³ is not present.k is 0, 1, 2 or 3;R¹ and R² and R³ are each independently selected from the groupconsisting of

(1) hydrogen,

(2) —C₁₋₆alkyl,

(3) —OC₁₋₆alkyl,

(4) —SC₁₋₆alkyl,

(5) —C₂₋₆alkenyl,

(6) —C₃₋₆cycloalkyl,

(7) aryl,

(8) heteroaryl,

(9) heterocyclic,

(10) —C₁₋₆alkylaryl,

(11) —C₁₋₆alkylheteroaryl

(12) —C₁₋₆alkylheterocyclic,

(13) —O-aryl,

(14) —O-heteroaryl,

(15) —O-heterocyclic,

(16) —OC₁₋₆alkylaryl,

(17) —OC₁₋₆alkylheteroaryl

(18) —OC₁₋₆alkylheterocyclic,

(19) halo,

(20) —CN,

(21) —NO₂,

(22) —C(O)—C₁₋₆alkyl,

(23) —C(O)-aryl,

(24) —C(O)-heteroaryl,

(25) —C(O)-heterocyclic,

(26) —C(O)—C₁₋₆alkyl,

(27) —NH—C₁₋₆alkyl,

(28) —N(C₁₋₆alkyl)(C₁₋₆alkyl)

(29) —C(O)—NH₂,

(30) —C(O)—NH—C₁₋₆alkyl,

(31) —C(O)—N(C₁₋₆alkyl)(C₁₋₆alkyl), and

(32) S(O)_(n)—C₁₋₆alkyl, wherein n is 1 or 2;

wherein definitions (1) to (18) and (22) to (32) are optionallysubstituted with 1, 2 or 3 substituents selected from the groupconsisting of halo, hydroxyl, —CN, —NO₂, NH₂;R⁴ and R⁵ are each independently selected from the group consisting of

(1) hydrogen,

(2) —C₁₋₆alkyl,

(3) —OC₁₋₆alkyl,

(4) —SC₁₋₆alkyl,

(5) —C₂₋₆alkenyl,

(6) —C₃₋₆cycloalkyl,

(7) aryl,

(8) heteroaryl,

(9) heterocyclic,

(10) —C₁₋₆alkylaryl,

(11) —C₁₋₆alkylheteroaryl

(12) —C₁₋₆alkylheterocyclic,

(13) —O-aryl,

(14) —O-heteroaryl,

(15) —O-heterocyclic,

(16) —OC₁₋₆alkylaryl,

(17) —OC₁₋₆alkylheteroaryl

(18) —OC₁₋₆alkylheterocyclic,

(19) halo,

(20) —CN,

(21) —NO₂,

(22) —C(O)—C₁₋₆alkyl,

(23) —C(O)-aryl,

(24) —C(O)-heteroaryl,

(25) —C(O)-heterocyclic,

(26) —C(O)—C₁₋₆alkyl,

(27) NH₂,

(28) —NH—C₁₋₆alkyl,

(29) —N(C₁₋₆alkyl)(C₁₋₆alkyl)

(30) —C(O)—NH₂,

(31) —C(O)—NH—C₁₋₆alkyl,

(32) —C(O)—N(C₁₋₆alkyl)(C₁₋₆alkyl),

(33) —SH, and

(34) S(O)n-C₁₋₆alkyl,

wherein definitions (1) to (18) and (22) to (32) and (34) are optionallysubstituted with 1, 2 or 3 substituents selected from the groupconsisting of halo, hydroxyl, —CN, —NO₂, NH₂;R₆ is hydrogen or C₁₋₃alkyl, optionally substituted with 1, 2 or 3substituents selected from

(1) -halo,

(2) —NR⁷R⁸,

(3) aryl,

(4) —OC₁₋₁₃alkyl,

(5) —SC₁₋₃alkyl, and

(6) —S(O)₂C₁₋₃alkyl,

(7) hydroxyl;

each R₇ and each R₈ are each independently hydrogen or C₁₋₃alkyl,optionally substituted with 1, 2 or 3 substituents selected from

(1) -halo,

(2) C₁₋₃alkyl,

(3) —OC₁₋₆alkyl,

(4) —SC₁₋₆alkyl,

(5) —S(O)₂C₁₋₆alkyl,

Ar is aryl or heteroaryl, optionally substituted with 1, 2 or 3substitutents selected from

(1) -halo,

(2) C₁₋₆alkyl, optionally substituted with 1, 2, 3 or 4 halo groups,

(3) —NR⁷R⁸,

(4) aryl,

(5) —OC₁₋₆alkyl, optionally substituted with 1, 2, 3 or 4 halo groups,

(6) —SC₁₋₆alkyl,

(7) —S(O)₂C₁₋₆alkyl;

Ar₁ is aryl or heteroaryl or C₃₋₆cycloalkyl, optionally substituted with1, 2 or 3 substitutents selected from

(1) -halo,

(2) C₁₋₆alkyl, optionally substituted with 1, 2, 3 or 4 halo groups,

(3) —NR⁷R⁸,

(4) aryl,

(5) —OC₁₋₆alkyl, optionally substituted with 1, 2, 3 or 4 halo groups,

(6) —SC₁₋₆alkyl, and

(7) —S(O)₂C₁₋₆alkyl;

provided that the compound of Formula I is other thanN-[4-(dimethylamino)benzyl]-N-(4-isopropylphenyl)-2-phenyl-5,6,7,8-tetrahydroquinoline-8-carboxamide.

Within this aspect there is a genus of compounds of Formula II, formulaIII and Formula IV:

Within this aspect there is a genus of compounds of Formula V, FormulaVI and Formula VII:

Within this aspect there is a genus of pounds of Formula VIII, FormulaIX and Formula X:

Within this aspect there is a genus of compounds wherein:

R¹ is selected from the group consisting of

(1) —C₁₋₆alkyl,

(2) —OC₁₋₆alkyl,

(3) —SC₁₋₆alkyl,

(4) —C₂₋₆alkenyl,

(5) —C₃₋₆cycloalkyl,

wherein definitions (1) to (5) are optionally substituted with 1, 2 or 3substituents selected from the group consisting of halo, hydroxyl, —CN,—NO₂, NH₂.

Within this aspect there is a genus of compounds wherein:

R² and R³ are each hydrogen.

Within this aspect there is a genus of compounds wherein:

R⁴ and R⁵ are each hydrogen.

Within this aspect there is a genus of compounds wherein:

R⁶ is hydrogen.

Within this aspect there is a genus of compounds wherein k is 1.

Within this aspect there is a genus of compounds wherein:

R¹ is selected from the group consisting of

(1) —C₁₋₃alkyl,

(2) —OC₁₋₃alkyl,

(3) —SC₁₋₃alkyl,

(4) —C₂₋₄alkenyl,

(5) —C₃₋₆cycloalkyl,

wherein definitions (1) to (5) are optionally substituted with 1, 2 or 3substituents selected from the group consisting of halo, hydroxyl, —CN,—NO₂, NH₂;R² and R³ are each hydrogen;R⁴ and R⁵ are each hydrogen;R⁶ is hydrogen,k is 1, andAr and Ar₁ are each independently an optionally substituted phenyl orpyridyl.

Within this aspect there is a genus of compounds of Formula II.

Within this genus is a class of compounds wherein:

R² and R³ are each hydrogen.

Within this genus there is a class of compounds wherein:

R⁴ and R⁵ are each hydrogen.

Within this genus there is a class of compounds wherein:

R⁶ is hydrogen.

Within this genus there is a class of compounds wherein k is 1.

Within this genus there is a class of compounds wherein:

R¹ is selected from the group consisting of

(1) —C₁₋₃alkyl,

(2) —OC₁₋₃alkyl,

(3) —SC₁₋₃alkyl,

(4) —C₂₋₄alkenyl,

(5) —C₃₋₆cycloalkyl,

wherein definitions (1) to (5) are optionally substituted with 1, 2 or 3substituents selected from the group consisting of halo, hydroxyl, —CN,—NO₂, NH₂;R² and R³ are each hydrogen;R⁴ and R⁵ are each hydrogen;R⁶ is hydrogen,k is 1, andAr and Ar₁ are each independently an optionally substituted phenyl orpyridyl.

Within this class, there is a sub-class of compounds wherein:

Ar and Ar₁ are each independently selected from phenyl optionallysubstituted with 1, 2 or 3 substituents selected from

(1) -halo,

(2) C₁₋₄alkyl, optionally substituted with 1, 2, 3 or 4 halo groups,

(3) —NR⁷R⁸,

(4) phenyl,

(5) —OC₁₋₄alkyl, optionally substituted with 1, 2, 3 or 4 halo groups,

(6) —SC₁₋₄alkyl; and

R⁷ and R⁸ are each independently hydrogen or methyl.

In another aspect the invention is directed to a pharmaceuticalcomposition comprising a compound of Formula I or a pharmaceuticallyacceptable salt thereof; and a pharmaceutically acceptable carrier.

In another aspect the invention is directed to a method of treatment orprevention of a C5a mediated disease or disorder comprisingadministering to a subject in need of such treatment or prevention, atherapeutically effective amount of Formula I or a pharmaceuticallyacceptable salt.

Within this aspect is a genus wherein the disease or disorder is animmunoregulatory disease or disorder.

Within this aspect there is a genus wherein the disease or disorder isan inflammatory disease or disorder.

Within this aspect there is a genus wherein the disease or disorder isrheumatoid arthritis, systemic lupus erythematosus, glomerulonephritis,ischemic heart diseases, reperfusion injury, sepsis, psoriasis,atherosclerosis, inflammatory bowel diseases, adult respiratory distresssyndrome, asthma, COPD and Alzheimer's disease.

Within this aspect there is a genus wherein the disease or disorder isan allergic disease, cardiac infarction, brain infarction, and seriousorgan injury due to activation of leukocytes caused by ischemiareperfusion, trauma, burn or surgical invasion.

In another aspect the invention is directed to a method of antagonizingC5a in a subject, comprising administering to a subject in need of suchantagonism, a therapeutically effective amount of a compound of FormulaI or a pharmaceutically acceptable salt.

Unless otherwise stated, the following terms have the meanings indicatedbelow:

As used herein, “alkyl” as well as other groups having the prefix “alk”such as, for example, alkoxy, alkanoyl, alkenyl, alkynyl and the like,means carbon chains which may be linear or branched or combinationsthereof. Examples of alkyl groups include methyl, ethyl, propyl,isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl and thelike. “Alkenyl”, “alkynyl” and other like terms include carbon chainscontaining at least one unsaturated C—C bond.

The term “haloalkyl”, such as “haloC₁₋₆alkyl”, means alkyl substitutedwith one or more halo groups.

The term “cycloalkyl” means carbocycles containing no heteroatoms, andincludes mono-, bi- and tricyclic saturated carbocycles, as well asfused ring systems. Such fused ring systems can include one ring that ispartially or fully unsaturated such as a benzene ring to form fused ringsystems such as benzofused carbocycles. Cycloalkyl includes such fusedring systems as spirofused ring systems. Examples of cycloalkyl includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthalene,adamantane, indanyl, indenyl, fluorenyl, 1,2,3,4-tetrahydronaphalene andthe like. Similarly, “cycloalkenyl” means carbocycles containing noheteroatoms and at least one non-aromatic C—C double bond, and includemono-, bi- and tricyclic partially saturated carbocycles, as well asbenzofused cycloalkenes. Examples of cycloalkenyl include cyclohexenyl,indenyl, and the like.

The term “cycloalkyloxy” unless specifically stated otherwise includes acycloalkyl group connected to the oxy connecting atom.

The term “alkoxy” unless specifically stated otherwise includes an alkylgroup connected to the oxy connecting atom.

The term “aryl” unless specifically stated otherwise includes multiplering systems as well as single ring systems such as, for example, phenylor naphthyl.

The term “aryloxy” unless specifically stated otherwise includesmultiple ring systems as well as single ring systems such as, forexample, phenyl or naphthyl, connected through the oxy connecting atomto the connecting site.

The term “C₀-C₆alkyl” includes alkyls containing 6, 5, 4, 3, 2, 1, or nocarbon atoms. An alkyl with no carbon atoms is a hydrogen atomsubstituent or a direct bond—depending on whether the alkyl is aterminus or a bridging moiety.

The term “hetero” unless specifically stated otherwise includes one ormore O, S, or N atoms. For example, heterocycloalkyl and heteroarylinclude ring systems that contain one or more O, S, or N atoms in thering, including mixtures of such atoms. The hetero atoms replace ringcarbon atoms. Thus, for example, a heterocycloC₅alkyl is a five memberedring containing from 5 to no carbon atoms.

Examples of heteroaryl include, for example, pyridinyl, quinolinyl,isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinoxalinyl, furyl,benzofuryl, dibenzofuryl, thienyl, benzothienyl, pyrrolyl, indolyl,pyrazolyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,imidazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl,tetrazolyl.

The term “heteroaryloxy” unless specifically stated otherwise describesa heteroaryl group connected through an oxy connecting atom to theconnecting site.

Examples of heteroaryl(C₁₋₆)alkyl include, for example, furylmethyl,furylethyl, thienylmethyl, thienylethyl, pyrazolylmethyl,oxazolylmethyl, oxazolylethyl, isoxazolylmethyl, thiazolylmethyl,thiazolylethyl, imidazolylmethyl, imidazolylethyl, benzimidazolylmethyl,oxadiazolylmethyl, oxadiazolylethyl, thiadiazolylmethyl,thiadiazolylethyl, triazolylmethyl, triazolylethyl, tetrazolylmethyl,tetrazolylethyl, pyridinylmethyl, pyridinylethyl, pyridazinylmethyl,pyrimidinylmethyl, pyrazinylmethyl, quinolinylmethyl,isoquinolinylmethyl and quinoxalinylmethyl.

Examples of heterocycloC₃₋₇alkyl include, for example, azetidinyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl,imidazolinyl, pyrrolidin-2-one, piperidin-2-one, and thiomorpholinyl.

Examples of aryl(C₁₋₆)alkyl include, for example, phenyl(C₁₋₆)alkyl, andnaphthyl(C₁₋₆)alkyl.

Examples of heterocycloC₃₋₇alkylcarbonyl(C₁₋₆)alkyl include, forexample, azetidinyl carbonyl(C₁₋₆)alkyl, pyrrolidinylcarbonyl(C₁₋₆)alkyl, piperidinyl carbonyl(C₁₋₆)alkyl, piperazinylcarbonyl(C₁₋₆)alkyl, morpholinyl carbonyl(C₁₋₆)alkyl, andthiomorpholinyl carbonyl(C₁₋₆)alkyl.

The term “amine” unless specifically stated otherwise includes primary,secondary and tertiary amines.

Unless otherwise stated, the term “carbamoyl” is used to include—NHC(O)OC₁-C₄alkyl, and —OC(O)NHC₁-C₄alkyl.

The term “halogen” includes fluorine, chlorine, bromine and iodineatoms.

The term “optionally substituted” is intended to include bothsubstituted and unsubstituted. Thus, for example, optionally substitutedaryl could represent a pentafluorophenyl or a phenyl ring. Further, thesubstitution can be made at any of the groups. For example, substitutedaryl(C₁₋₆)alkyl includes substitution on the aryl group as well assubstitution on the alkyl group.

The term “oxide” of heteroaryl groups is used in the ordinary well-knownchemical sense and include, for example, N-oxides of nitrogenheteroatoms.

Compounds described herein contain one or more double bonds and may thusgive rise to cis/trans isomers as well as other conformational isomers.The present invention includes all such possible isomers as well asmixtures of such isomers.

Compounds described herein can contain one or more asymmetric centersand may thus give rise to diastereomers and optical isomers. The presentinvention includes all such possible diastereomers as well as theirracemic mixtures, their substantially pure resolved enantiomers, allpossible geometric isomers, and pharmaceutically acceptable saltsthereof. The above Formula I is shown without a definitivestereochemistry at certain positions. The present invention includes allstereoisomers of Formula I and pharmaceutically acceptable saltsthereof. Further, mixtures of stereoisomers as well as isolated specificstereoisomers are also included. During the course of the syntheticprocedures used to prepare such compounds, or in using racemization orepimerization procedures known to those skilled in the art, the productsof such procedures can be a mixture of stereoisomers.

Salts

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids. When thecompound of the present invention is acidic, its corresponding salt canbe conveniently prepared from pharmaceutically acceptable non-toxicbases, including inorganic bases and organic bases. Salts derived fromsuch inorganic bases include aluminum, ammonium, calcium, copper (ic andous), ferric, ferrous, lithium, magnesium, manganese (ic and ous),potassium, sodium, zinc and the like salts. Preferred are the ammonium,calcium, magnesium, potassium and sodium salts. Salts prepared frompharmaceutically acceptable organic non-toxic bases include salts ofprimary, secondary, and tertiary amines derived from both naturallyoccurring and synthetic sources. Pharmaceutically acceptable organicnon-toxic bases from which salts can be formed include, for example,arginine, betaine, caffeine, choline, N,N′-dibenzylethylenediamine,diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol,ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine,glucamine, glucosamine, histidine, hydrabamine, isopropylamine,dicyclohexylamine, lysine, methylglucamine, morpholine, piperazine,piperidine, polyamine resins, procaine, purines, theobromine,triethylamine, trimethylamine, tripropylamine, tromethamine and thelike.

When the compound of the present invention is basic, its correspondingsalt can be conveniently prepared from pharmaceutically acceptablenon-toxic inorganic and organic acids. Such acids include, for example,acetic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic,nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric,p-toluenesulfonic acid and the like. Preferred are citric, hydrobromic,hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.

Prodrugs

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds of this invention which arereadily convertible in vivo into the required compound. Thus, in themethods of treatment of the present invention, the term “administering”shall encompass the treatment of the various conditions described withthe compound specifically disclosed or with a compound which may not bespecifically disclosed, but which converts to the specified compound invivo after administration to the patient. Conventional procedures forthe selection and preparation of suitable prodrug derivatives aredescribed, for example, in “Design of Prodrugs,” ed. H. Bundgaard,Elsevier, 1985. Metabolites of these compounds include active speciesproduced upon introduction of compounds of this invention into thebiological milieu.

Pharmaceutical Compositions

Another aspect of the present invention provides pharmaceuticalcompositions which comprises a compound of Formula I and apharmaceutically acceptable carrier. The term “composition”, as inpharmaceutical composition, is intended to encompass a productcomprising the active ingredient(s), and the inert ingredient(s)(pharmaceutically acceptable excipients) that make up the carrier, aswell as any product which results, directly or indirectly, fromcombination, complexation or aggregation of any two or more of theingredients, or from dissociation of one or more of the ingredients, orfrom other types of reactions or interactions of one or more of theingredients. Accordingly, the pharmaceutical compositions of the presentinvention encompass any composition made by admixing a compound ofFormula I, additional active ingredient(s), and pharmaceuticallyacceptable excipients.

The pharmaceutical compositions of the present invention comprise acompound represented by Formula I (or pharmaceutically acceptable saltsthereof) as an active ingredient, a pharmaceutically acceptable carrierand optionally other therapeutic ingredients or adjuvants. Thecompositions include compositions suitable for oral, rectal, topical,and parenteral (including subcutaneous, intramuscular, and intravenous)administration, although the most suitable route in any given case willdepend on the particular host, and nature and severity of the conditionsfor which the active ingredient is being administered. Thepharmaceutical compositions may be conveniently presented in unit dosageform and prepared by any of the methods well known in the art ofpharmacy.

In practice, the compounds represented by Formula I, or pharmaceuticallyacceptable salts thereof, of this invention can be combined as theactive ingredient in intimate admixture with a pharmaceutical carrieraccording to conventional pharmaceutical compounding techniques. Thecarrier may take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral(including intravenous). Thus, the pharmaceutical compositions of thepresent invention can be presented as discrete units suitable for oraladministration such as capsules, cachets or tablets each containing apredetermined amount of the active ingredient. Further, the compositionscan be presented as a powder, as granules, as a solution, as asuspension in an aqueous liquid, as a non-aqueous liquid, as anoil-in-water emulsion or as a water-in-oil liquid emulsion. In additionto the common dosage forms set out above, the compound represented byFormula I, or pharmaceutically acceptable salts thereof, may also beadministered by controlled release means and/or delivery devices. Thecompositions may be prepared by any of the methods of pharmacy. Ingeneral, such methods include a step of bringing into association theactive ingredient with the carrier that constitutes one or morenecessary ingredients. In general, the compositions are prepared byuniformly and intimately admixing the active ingredient with liquidcarriers or finely divided solid carriers or both. The product can thenbe conveniently shaped into the desired presentation.

Thus, the pharmaceutical compositions of this invention may include apharmaceutically acceptable carrier and a compound or a pharmaceuticallyacceptable salt of Formula I. The compounds of Formula I, orpharmaceutically acceptable salts thereof, can also be included inpharmaceutical compositions in combination with one or more othertherapeutically active compounds.

The pharmaceutical carrier employed can be, for example, a solid,liquid, or gas. Examples of solid carriers include lactose, terra alba,sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, andstearic acid. Examples of liquid carriers are sugar syrup, peanut oil,olive oil, and water. Examples of gaseous carriers include carbondioxide and nitrogen.

In preparing the compositions for oral dosage form, any convenientpharmaceutical media may be employed. For example, water, glycols, oils,alcohols, flavoring agents, preservatives, coloring agents and the likemay be used to form oral liquid preparations such as suspensions,elixirs and solutions; while carriers such as starches, sugars,microcrystalline cellulose, diluents, granulating agents, lubricants,binders, disintegrating agents, and the like may be used to form oralsolid preparations such as powders, capsules and tablets. Because oftheir ease of administration, tablets and capsules are the preferredoral dosage units whereby solid pharmaceutical carriers are employed.Optionally, tablets may be coated by standard aqueous or nonaqueoustechniques

A tablet containing the composition of this invention may be prepared bycompression or molding, optionally with one or more accessoryingredients or adjuvants. Compressed tablets may be prepared bycompressing, in a suitable machine, the active ingredient in afree-flowing form such as powder or granules, optionally mixed with abinder, lubricant, inert diluent, surface active or dispersing agent.Molded tablets may be made by molding in a suitable machine, a mixtureof the powdered compound moistened with an inert liquid diluent. Eachtablet preferably contains from about 0.1 mg to about 500 mg of theactive ingredient and each cachet or capsule preferably containing fromabout 0.1 mg to about 500 mg of the active ingredient.

Pharmaceutical compositions of the present invention suitable forparenteral administration may be prepared as solutions or suspensions ofthe active compounds in water. A suitable surfactant can be includedsuch as, for example, hydroxypropylcellulose. Dispersions can also beprepared in glycerol, liquid polyethylene glycols, and mixtures thereofin oils. Further, a preservative can be included to prevent thedetrimental growth of microorganisms.

Pharmaceutical compositions of the present invention suitable forinjectable use include sterile aqueous solutions or dispersions.Furthermore, the compositions can be in the form of sterile powders forthe extemporaneous preparation of such sterile injectable solutions ordispersions. In all cases, the final injectable form must be sterile andmust be effectively fluid for easy syringability. The pharmaceuticalcompositions must be stable under the conditions of manufacture andstorage; thus, preferably should be preserved against the contaminatingaction of microorganisms such as bacteria and fungi. The carrier can bea solvent or dispersion medium containing, for example, water, ethanol,polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol),vegetable oils, and suitable mixtures thereof.

Pharmaceutical compositions of the present invention can be in a formsuitable for topical use such as, for example, an aerosol, cream,ointment, lotion, dusting powder, or the like. Further, the compositionscan be in a form suitable for use in transdermal devices. Theseformulations may be prepared, utilizing a compound represented byFormula I of this invention, or pharmaceutically acceptable saltsthereof, via conventional processing methods. As an example, a cream orointment is prepared by mixing hydrophilic material and water, togetherwith about 5 wt % to about 10 wt % of the compound, to produce a creamor ointment having a desired consistency.

Pharmaceutical compositions of this invention can be in a form suitablefor rectal administration wherein the carrier is a solid. It ispreferable that the mixture forms unit dose suppositories. Suitablecarriers include cocoa butter and other materials commonly used in theart. The suppositories may be conveniently formed by first admixing thecomposition with the softened or melted carrier(s) followed by chillingand shaping in moulds.

In addition to the aforementioned carrier ingredients, thepharmaceutical formulations described above may include, as appropriate,one or more additional carrier ingredients such as diluents, buffers,flavoring agents, binders, surface-active agents, thickeners,lubricants, preservatives (including anti-oxidants) and the like.Furthermore, other adjuvants can be included to render the formulationisotonic with the blood of the intended recipient. Compositionscontaining a compound described by Formula I, or pharmaceuticallyacceptable salts thereof, may also be prepared in powder or liquidconcentrate form.

The following are examples of representative pharmaceutical dosage formsfor the compounds of Formula I:

Injectable Suspension (I.M.) mg/mL Compound of Formula I10Methylcellulose 5.0 Tween 80 0.5 Benzyl alcohol 9.0 Benzalkoniumchloride 1.0 Water for injection to a total volume of 1 mL Tabletmg/tablet Compound of Formula I25 Microcrystalline Cellulose 415Povidone 14.0 Pregelatinized Starch 43.5 Magnesium Stearate 2.5 500Capsule mg/capsule Compound of Formula I25 Lactose Powder 573.5Magnesium Stearate 1.5 600

Utilities

Compounds described in this invention are antagonists of the C5areceptor. The ability of the compounds described in this invention tointeract with the C5a receptor makes them useful for preventing orreversing undesirable symptoms caused by C5a in a mammalian, especiallyhuman subject. The antagonism of the actions of C5a indicates that thecompounds and pharmaceutical compositions thereof are useful to treat,prevent, or ameliorate in mammals and especially in humans: respiratoryconditions, allergic conditions, inflammatory conditions,neurodegenerative conditions as well as immune and autoimmune diseases.

Accordingly, another aspect of the invention provides a method oftreating or preventing a C5a mediated disease comprising administeringto a mammalian patient in need of such treatment a compound described inthis invention in an amount which is effective for treating orpreventing said C5a-mediated disease. C5a-mediated diseases include, butare not limited to rheumatoid arthritis, systemic lupus erythematosus,glomerulonephritis, ischemic heart diseases, reperfusion injury, sepsis,psoriasis, atherosclerosis, inflammatory bowel diseases (IBD), adultrespiratory distress syndrome (ARDS), asthma, chronic obstructivepulmonary disease (COPD) and Alzheimer's disease.

Assay for the Evaluation of Biological Activity

Compounds of Formula I can be tested using the following assays todetermine their antagonist or agonist activity in vitro.

C5a Receptor Competitive Binding Assay

The full length coding sequence of C5a receptor (C5aR) is subcloned intothe appropriate site of a mammalian expression vector and transfectedinto rat basophilic leukemia (RBL) cell line-2H3. The RBL cellsexpressing the C5aR are grown under selection, individual colonies areisolated after 2-3 weeks of growth and subsequently expanded into clonalcell lines.

A selected clonal RBL cell line expressing the C5aR is maintained inculture and harvested. Membranes are collected by differentialcentrifugation following lysis of the cells by nitrogen cavitation inthe presence of protease inhibitors. To a test mixture comprising 0.25μg of membranes mixed with 70 pM of ¹²⁵I-C5a (Specific activity: 2200Ci/mMole; from Perkin Elmer) in 75 μl of assay buffer (Hanks BalancedSalt buffered Saline with 10 mM Hepes containing 0.25% bovine serumalbumin) a test compound is added at concentrations ranging from 0.1 nMto 10 μM. After a 90 minutes incubation at room temperature, the testmixture is filtered using a TOMTEC harvester over Packard GF/C filters(or equivalent) and the filter washed using 50 mM MES, pH 5.5 washbuffer. The non-specific background is measured by the addition of 35 nMof unlabelled C5a (from Calbiochem) to the test mixture in the absenceof the test compound.

Whole Cell Assays to Determine C5a Receptor Agonists and Antagonists I.Enzyme Release Assay

In order to increase the expression of C5aR the monocytic cell line U937is differentiated by incubating the cells in the presence of 1 mMdibutyryl cAMP for 72 hours. The differentiated U937 cells (dU937) areharvested and resuspended in the assay buffer (Hank's balanced saltsolution+10 mM Hepes+0.25% bovine serum albumin) and 125,000 cells perwell are distributed onto Millipore multiscreen 1.2μ durapore plates.The dU937 cells are then stimulated for 3 minutes at 37° C. in presenceof 10 nM C5a in the assay buffer described above. The presence of C5a inthis assay causes the release of the lysosomal enzymeN-acetyl-β-D-glucosaminidase from the cells into the assay buffer. Atthe end of the stimulation, the assay buffer is separated from the cellsby applying vacuum to the multiscreen plates. The amount of enzymereleased in the assay buffer is determined by a simple colorimetricassay. To the assay buffer, 8 mM of 4-nitrophenylN-acetyl-β-D-glucosaminide substrate is added and incubated for 90minutes at 37° C. The reaction is quenched with the addition of a 1:5dilution of a stop buffer (1.2M glycine/NaoH pH 10.4), the colordeveloped is determined at an absorbance of 405 nm. To evaluate theantagonist activity, the test compound is pre-incubated atconcentrations ranging from 0.1 nM to 2 μM with the cells for 20 minutesat 37° C. prior to the addition of C5a. To determine if the testcompound has agonist activity, the compound is added to the cells at aconcentration of 10 μM for 3 minutes at 37° C.

II Calcium Mobilization Assay

RBL clonal cells expressing the C5aR are plated at 45,000 cells per wellin a 96-well plate and incubated 24 hours prior to the assay. Into eachwell, 100 ul of the cytoplasmic calcium indicator (no wash dye fromMolecular Devices) is added and the plates are incubated for anadditional 45 minutes at 37° C. Changes in cell fluorescence aremonitored before and after the addition of 2 nM C5a using a FLIPR™(Molecular Devices) at λ_(ex)=488 nm and λ_(em)=540 nm. To determine theantagonist activity, the test compound is pre-incubated atconcentrations ranging from 0.01 nM to 10 μM with the cells for 10minutes at 37° C. prior to the addition of C5a. To determine if the testcompound has agonist activity, the compound is added to the cells at aconcentration of 10 μM and changes in fluorescence monitored.

Determination of Ligand Agonist Activity Microphysiometry

The assay measures the change in the acidification in the cell mediawhen a ligand binds to a C5aR, activating cellular metabolism. Briefly,RBL clonal cells expressing the C5aR are incubated overnight at 37° C.in a Cytosensor cell capsule cup (Molecular Devices). The cup is placedin the sensor chamber of the microphysiometer (Molecular Devices). Thesensor monitors the voltage change in the chamber, which is proportionalto the concentration of H⁺ ions produced as a result of increasedcellular metabolism. Cells are exposed to various concentrations of atest compound and an increase in the rate of voltage change in thechamber indicates agonist activity.

C5a Receptor Antagonist Whole Blood Assay

The assay is based on the capacity of exogenous C5a to stimulate therelease of IL-6 in human or primate whole blood.

Blood collected into tubes containing an anti-coagulant (heparin; 14U/ml blood) is pre-incubated in the presence of a carboxypeptidase Ninhibitor at a final concentration of 100 nM at 37° C. for 15 minutes(carboxypeptidase N inhibitor prevents the removal of thecarboxy-terminal arginine on C5a by proteases in the blood which isnecessary for optimal activity of the ligand). C5a is then added to afinal concentration of 45 nM and the blood is incubated at 37° C. for 24hours. The blood is then centrifuged at 1500 g for 15 minutes at 4° C.and the amount of IL-6 in the plasma is determined by ELISA (fromBioSouce). To determine the antagonist activity, the test compound ispre-incubated with the carboxypeptidase N inhibitor for 15 minutes at37° C. at concentrations ranging from 0.001 nM to 10 μM prior to theaddition of C5a.

The invention will now be illustrated in the following non-limitingExamples in which, unless otherwise stated:

-   1. All the end products of the formula I were analyzed by NMR, TLC.-   2. Intermediates were analyzed by NMR and/or TLC.-   3. Most compounds were purified by flash chromatography on silica    gel, recrystallization and/or swish (suspension in a solvent    followed by filtration of the solid).-   4. The course of reactions was followed by thin layer chromatography    (TLC) and reaction times are given for illustration only.

The following intermediates were prepared according to literatureprocedures or purchased from the following vendor:

5,6,7,8-Tetrahydroquinolin-2(1H)-one: (a) Cappelli, A.; Anzini, M.;Vomero, S.; Mennuni, L.; Makovec, F.; Doucet, E.; Hamon, M.; Bruni, G.;Romeo, M. R.; Menziani, M. C.; De Benedetti, P. G.; Langer, T. J. Med.Chem. 1998; 41, 728-741. (b) Meyers, A. I.; Garcia-Munoz, G. J. Org.Chem. 1964; 29, 1435-1438.1,5,6,7-Tetrahydro-2H-cyclopenta[b]pyridin-2-one: Cappelli, A.; Anzini,M.; Vomero, S.; Mennuni, L.; Makovec, F.; Doucet, E.; Hamon, M.; Bruni,G.; Romeo, M. R.; Menziani, M. C.; De Benedetti, P. G.; Langer, T. J.Med. Chem. 1998; 41, 728-741.2-Methyl-5,6,7,8-tetrahydroquinoline: TCI2-Chloro-5,6,7,8-tetrahydroquinoline: Zimmerman, S. C.; Zeng, Z; Wu, W.;Reichert, D. E. J. Am. Chem. Soc. 1991; 113, 183-196.

Method A

An appropriately substituted benzaldehyde 1 is reductively aminated withaniline 2 using a reducing agent such as NaB(OAc)₃H to give thecorresponding N-benzylaniline 3.

Method B

Pyridine-2-one 4 (ref. 1, 2) is alkylated with an alkyl iodide R^(b)Iand a suitable silver salt such as Ag₂ CO₃ to give alkoxypyridine 5.Treatment with a strong base such as t-BuLi in THF or Et₂O gives theanion which is quenched with CO₂ (g). After removal of the solvent, theintermediate lithium carboxylate and an appropriate amine 3 are treatedwith a suitable coupling reagent such as T3P and a suitable base such asN-methylmorpholine in DMF to give the corresponding amide 6.

Method C

Quinaldine is treated with a suitable strong base such as LDA and analkylating agent R^(c)X to give alkylquinoline 8. Hydrogenation over asuitable catalyst such as PtO₂ in a solvent such as TFA overnight givespyridine 9. Treatment with a strong base such as t-BuLi in THF or Et₂Ogives the anion which is quenched with CO₂ (g). After removal of thesolvent, the intermediate lithium carboxylate and an appropriate amine 3are treated with a suitable coupling reagent such as T3P and a suitablebase such as N-methylmorpholine in DMF to give the corresponding amide10.

Method D

Alkylquinoline 8 is treated with a suitable strong base such as LDA andan alkylating agent R^(d)X to give alkylquinoline 11. Hydrogenation overa suitable catalyst such as PtO₂ in a solvent such as TFA overnightgives pyridine 12. Treatment with a strong base such as t-BuLi in THF orEt₂O gives the anion which is quenched with CO₂ (g). After removal ofthe solvent, the intermediate lithium carboxylate and an appropriateamine 3 are treated with a suitable coupling reagent such as T3P and asuitable base such as N-methylmorpholine in DMF to give thecorresponding amide 13.

Method E

2-Halocycloalkylpyridine 14 is treated with an alkyl thiolate in NMP togive thioether 15. Treatment with a strong base such as t-BuLi in THF orEt₂O gives the anion which is quenched with CO₂ (g). After removal ofthe solvent, the intermediate lithium carboxylate and an appropriateamine 3 are treated with a suitable coupling reagent such as T3P and asuitable base such as N-methylmorpholine in DMF to give thecorresponding amide 16.

EXAMPLE 1 A (+) or(−)-N-[4-(Dimethylamino)benzyl]-N-(4-isopropylphenyl)-2-methoxy-5,6,7,8-tetrahydroquinoline-8-carboxamide(Enantiomer A)

Step 1. N-[4-(Dimethylamino)benzyl]-4-isopropylaniline

To a 0.33 M solution of 4-(dimethylamino)benzaldehyde in THF at 0° C.was added 1.1 equiv of 4-isopropylaniline followed by 1.5 equiv ofsodium triacetoxyborohydride. After allowing the reaction to warm toroom temperature overnight, this mixture was poured into a separatoryfunnel containing aqueous NH₄Cl/EtOAc. The organic layer was washed withbrine, dried over anhydrous Na₂SO₄, filtered and concentrated. The crudematerial was further purified by flash chromatography, eluting with agradient from 100% hexanes to 10% EtOAc/hexanes to provide the titlecompound as a white solid.

¹H NMR (acetone-d₆) δ 7.23 (2H, d), 6.97 (2H, d), 6.73 (2H, d), 6.61(2H, d), 5.03 (1H, br s), 4.19 (2H, d), 2.91 (6H, s), 2.76 (1H, m), 1.17(6H, d).

Step 2. 2-Methoxy-5,6,7,8-tetrahydroquinoline

To a 0.33 M solution of 5,6,7,8-tetrahydroquinolin-2(1H)-one in dryCHCl₃ at room temperature was added 1.2 equiv of Ag₂CO₃ and 6 equiv ofMeI. The final suspension was refluxed in the dark for 5 h. Afterallowing the reaction to cool to room temperature, the suspension wasfiltered through Celite and concentrated. The crude material was furtherpurified by flash chromatography, eluting with a gradient from 100%hexanes to 10% EtOAc/hexanes to provide the title compound as acolorless oil.

¹H NMR (acetone-d₆) δ 7.32 (1H, d), 6.50 (1H, d), 3.83 (3H, s), 2.74(2H, m), 2.67 (2H, m), 1.84 (2H, m), 1.78 (2H, m).

Step 3.(+/−)-N-[4-(Dimethylamino)benzyl]-N-(4-isopropylphenyl)-2-methoxy-5,6,7,8-tetrahydroquinoline-8-carboxamide

To a 0.22 M solution of 2-methoxy-5,6,7,8-tetrahydroquinoline in Et₂O at−78° C. was added 1.7 equiv of t-BuLi [1.7M] over 5 min. After allowingthe reaction to warm up to 0° C. and stirring at this temperature for 30min, a stream of CO₂ (g) was then allowed to flow into the flask. Thefinal mixture was allowed to warm to room temperature and the solventwas removed by the flow of CO₂. To a solution/suspension of theresulting crude lithium carboxylate salt in DMF (12 equiv) at 0° C. wassuccessively added 1.2 equiv ofN-[4-(dimethylamino)benzyl]-4-isopropylaniline, 12 equiv of4-methylmorpholine and 4.0 equiv of 1-propylphosphonic acid cyclicanhydride (50% in EtOAc). After allowing the reaction to warm to roomtemperature overnight, this mixture was poured into a separatory funnelcontaining aqueous NaHCO₃/EtOAc. The organic layer was washed withbrine, dried over anhydrous MgSO₄, filtered and concentrated. The crudematerial was further purified by flash chromatography, eluting with agradient from 100% hexanes to 25% EtOAc/hexanes to provide the titlecompound as a white solid.

¹H NMR (acetone-d₆) δ 7.36-7.31 (3H, m), 7.28 (2H, d), 7.14 (2H, d),6.65 (2H, d), 6.53 (1H, d), 5.20 (1H, d), 4.51 (1H, d), 3.87-3.82 (4H,m), 2.95-2.88 (7H, m), 2.71 (1H, m), 2.58 (1H, m), 2.08-2.02 (2H, m),1.94 (1H, m), 1.46 (1H, m), 1.23 (6H, d).

Step 4. (+) or(−)-N-[4-(Dimethylamino)benzyl]-N-(4-isopropylphenyl)-2-methoxy-5,6,7,8-tetrahydroquinoline-8-carboxamide(Enantiomer A)

The enantiomers were then separated on a Chiralcel OD column (2×25 cm)eluting with 1:10 isopropanol:hexane at a flow rate of 6 mL/min and awavelength of 254 nm. The first eluting isomer (Example 1A) had aretention time of 24.0 min, and the second eluting isomer (Example 1B)had a retention time of 31.6 min.

¹H NMR (acetone-d₆) δ 7.36-7.31 (3H, m), 7.28 (2H, d), 7.14 (2H, d),6.65 (2H, d), 6.53 (1H, d), 5.20 (1H, d), 4.51 (1H, d), 3.87-3.82 (4H,m), 2.95-2.88 (7H, m), 2.71 (1H, m), 2.58 (1H, m), 2.08-2.02 (2H, m),1.94 (1H, m), 1.46 (1H, m), 1.23 (6H, d).

EXAMPLE 1 B (−) or(+)-N-[4-(Dimethylamino)benzyl]-N-(4-isopropylphenyl)-2-methoxy-5,6,7,8-tetrahydroquinoline-8-carboxamide(Enantiomer B)

The title compound was obtained as the second eluting isomer (retentiontime of 31.6 min) from the chromatography described in Example 1A, Step4.

¹H NMR (acetone-d₆) δ 7.36-7.31 (3H, m), 7.28 (2H, d), 7.14 (2H, d),6.65 (2H, d), 6.53 (1H, d), 5.20 (1H, d), 4.51 (1H, d), 3.87-3.82 (4H,m), 2.95-2.88 (7H, m), 2.71 (1H, m), 2.58 (1H, m), 2.08-2.02 (2H, m),1.94 (1H, m), 1.46 (1H, m), 1.23 (6H, d).

EXAMPLE 2(+/−)-N-[4-(Dimethylamino)benzyl]-N-(4-isopropylphenyl)-2-methoxy-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carboxamide

Step 1. 2-Methoxy-6,7-dihydro-5H-cyclopenta[b]pyridine

Following the procedure described in Example 1 A, step 2,1,5,6,7-tetrahydro-2H-cyclopenta[b]pyridin-2-one and MeI gave the titlecompound as a colorless oil.

¹H NMR (CDCl₃) δ 7.37 (1H, d), 6.47 (1H, d), 3.90 (3H, s), 2.91 (2H, t),2.82 (2H, t), 2.09 (2H, quint).

Step 2.(+/−)-N-[4-(Dimethylamino)benzyl]-N-(4-isopropylphenyl)-2-methoxy-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carboxamide

Following the procedure described in Example 1 A, step 3, using2-methoxy-6,7-dihydro-5H-cyclopenta[b]pyridine, andN-[4-(dimethylamino)benzyl]-4-isopropylaniline gave the title compoundas a colorless oil.

¹H NMR (acetone-d₆) δ 7.50 (1H, d), 7.43 (2H, m), 7.27 (2H, d), 7.15(2H, d), 6.66 (2H, d), 6.57 (1H, d), 5.30 (1H, d), 4.49 (1H, d),4.05-4.02 (1H, m), 3.94 (3H, s), 3.00-2.89 (8H, m), 2.72 (1H, m), 2.51(1H, m), 2.16 (1H, m), 1.22 (6H, d).

EXAMPLE 3(+/−)-N-(4-Chlorobenzyl)-N-(4-isopropylphenyl)-2-methoxy-5,6,7,8-tetrahydroquinoline-8-carboxamide

Step 1. N-(4-Chlorobenzyl)-4-isopropylaniline

Following the procedure described in Example 1 A, step 1,4-chlorobenzaldehyde and 4-isopropylaniline gave the title compound asan off-white solid.

¹H NMR (acetone-d₆) δ 7.43 (2H, d), 7.35 (2H, d), 6.98 (2H, d), 6.58(2H, d), 5.38 (1H, br s), 4.35 (2H, d), 2.75 (1H, m), 1.17 (6H, d).

Step 2.(+/−)-N-(4-Chlorobenzyl)-N-(4-isopropylphenyl)-2-methoxy-5,6,7,8-tetrahydroquinoline-8-carboxamide

Following the procedure described in Example 1 A, step 3, using2-methoxy-5,6,7,8-tetrahydroquinoline, andN-(4-chlorobenzyl)-4-isopropylaniline gave the title compound as a foam.

¹H NMR (acetone-d₆) δ 7.41-7.30 (9H, m), 6.55 (1H, d), 5.32 (1H, d),4.62 (1H, d), 3.91-3.86 (4H, m), 2.92 (1H, sept), 2.71 (1H, m), 2.59(1H, m), 2.10-1.94 (3H, m), 1.46 (1H, m), 1.22 (6H, d).

EXAMPLE 4(+/−)-N-(4-Isopropylbenzyl)-N-(4-isopropylphenyl)-2-methoxy-5,6,7,8-tetrahydroquinoline-8-carboxamide

Step 1. (4-Isopropylbenzyl)(4-isopropylphenyl)amine

Following the procedure described in Example 1 A, step 1,4-isopropylbenzaldehyde and 4-isopropylaniline gave the title compoundas a colorless oil.

¹H NMR (acetone-d₆) δ 7.32 (2H, d), 7.21 (2H, d), 6.98 (2H, d), 6.61(2H, d), 5.22 (1H, br s), 4.29 (2H, d), 2.90 (1H, s), 2.76 (1H, m), 1.23(6H, d), 1.17 (6H, d).

Step 2.(+/−)-N-(4-Isopropylbenzyl)-N-(4-isopropylphenyl)-2-methoxy-5,6,7,8-tetrahydroquinoline-8-carboxamide

Following the procedure described in Example 1 A, step 3, using2-methoxy-5,6,7,8-tetrahydroquinoline, and(4-isopropylbenzyl)(4-isopropylphenyl)amine gave the title compound as afoam.

¹H NMR (acetone-d₆) δ 7.40 (2H, m), 7.33 (1H, d), 7.30-7.26 (4H, m),7.16 (2H, d), 6.54 (1H, d), 5.30 (1H, d), 4.59 (1H, d), 3.90-3.85 (4H,m), 2.94-2.86 (2H, m), 2.71 (1H, m), 2.60 (1H, m), 2.09-2.03 (2H, m),1.96 (1H, m), 1.47 (1H, m), 1.23 (6H, d), 1.22 (6H, d).

EXAMPLE 5(+/−)-N-(Biphenyl-4-ylmethyl)-N-(4-isopropylphenyl)-2-methoxy-5,6,7,8-tetrahydroquinoline-8-carboxamide

Step 1. N-(Biphenyl-4-ylmethyl)-4-isopropylaniline

Following the procedure described in Example 1 A, step 1, 4-biphenylcarboxaldehyde and 4-isopropylaniline gave the title compound as a whitesolid.

¹H NMR (acetone-d₆) δ 7.67 (2H, m), 7.63 (2H, d), 7.51 (2H, d), 7.46(2H, t), 7.36 (1H, t), 6.99 (2H, d), 6.63 (2H, d), 5.37 (1H, br s), 4.40(2H, d), 2.77 (1H, m), 1.17 (6H, d).

Step 2.(+/−)-N-(Biphenyl-4-ylmethyl)-N-(4-isopropylphenyl)-2-methoxy-5,6,7,8-tetrahydroquinoline-8-carboxamide

Following the procedure described in Example 1 A, step 3, using2-methoxy-5,6,7,8-tetrahydroquinoline, andN-(biphenyl-4-ylmethyl)-4-isopropylaniline gave the title compound as acolorless oil which gradually solidified.

¹H NMR (acetone-d₆) δ 7.66 (2H, d), 7.59 (2H, d), 7.48-7.44 (6H, m),7.38-7.30 (4H, m), 6.55 (1H, d), 5.40 (1H, d), 4.68 (1H, d), 3.93-3.90(4H, m), 2.95-2.90 (1H, m), 2.76-2.70 (1H, m), 2.62-2.57 (1H, m),2.13-2.03 (2H, m), 2.00-1.97 (1H, m), 1.49-1.46 (1H, m), 1.22 (6H, d).

EXAMPLE 6(+/−)-N-(4-isopropylphenyl)-2-methoxy-N-[4-(trifluoromethyl)benzyl]-5,6,7,8-tetrahydroquinoline-8-carboxamide

Step 1. (4-Isopropylphenyl)[4-(trifluoromethyl)benzyl]amine

Following the procedure described in Example 1 A, step 1,4-(trifluoromethyl)benzaldehyde and 4-isopropylaniline gave the titlecompound as a pale yellow oil.

¹H NMR (acetone-d₆) δ 7.68 (2H, d), 7.64 (2H, d), 6.98 (2H, d), 6.58(2H, d), 5.52 (1H, br s), 4.48 (2H, d), 2.79-2.73 (1H, m), 1.17 (6H, d).

Step 2.(+/−)-N-(4-isopropylphenyl)-2-methoxy-N-[4-(trifluoromethyl)benzyl]-5,6,7,8-tetrahydroquinoline-8-carboxamide

Following the procedure described in Example 1 A, step 3, using2-methoxy-5,6,7,8-tetrahydroquinoline, and(4-isopropylphenyl)[4-(trifluoromethyl)benzyl]amine gave the titlecompound as a foam.

¹H NMR (acetone-d₆) δ 7.65 (2H, d), 7.59 (2H, d), 7.44 (2H, d),7.36-7.31 (3H, m), 6.56 (1H, d), 5.41 (1H, d), 4.77 (1H, d), 3.92-3.88(4H, m), 2.96-2.90 (1H, m), 2.75-2.69 (1H, m), 2.63-2.58 (1H, m),2.11-1.97 (3H, m), 1.50-1.46 (1H, m), 1.22 (6H, d).

EXAMPLE 7(+/−)-N-(4-Isopropylphenyl)-2-methoxy-N-(4-methoxybenzyl)-5,6,7,8-tetrahydroquinoline-8-carboxamide

Step 1. (4-Isopropylphenyl)(4-methoxybenzyl)amine

Following the procedure described in Example 1 A, step 1,4-methoxybenzaldehyde and 4-isopropylaniline gave the title compound asa foam.

¹H NMR (acetone-d₆) δ 7.29 (2H, d), 6.95 (2H, d), 6.86 (2H, d), 6.57(2H, d), 5.16 (1H, br s), 4.23 (2H, d), 3.75 (3H, s), 2.73 (1H, sept),1.14 (6H, d).

Step 2.(+/−)-N-(4-Isopropylphenyl)-2-methoxy-N-(4-methoxybenzyl)-5,6,7,8-tetrahydroquinoline-8-carboxamide

Following the procedure described in Example 1 A, step 3, using2-methoxy-5,6,7,8-tetrahydroquinoline, and(4-isopropylphenyl)(4-methoxybenzyl)amine gave the title compound as afoam.

¹H NMR (acetone-d₆) δ 7.37-7.33 (3H, m), 7.29 (2H, d), 7.24 (2H, d),6.84 (2H, d), 6.54 (1H, d), 5.26 (1H, d), 4.55 (1H, d), 3.89-3.83 (4H,m), 3.78 (3H, s), 2.92 (1H, sept), 2.75-2.69 (1H, m), 2.62-2.57 (1H, m),2.09-2.03 (2H, m), 1.98-1.94 (1H, m), 1.50-1.43 (1H, m), 1.23 (6H, d).

EXAMPLE 8(+/−)-N-(4-Isopropylphenyl)-2-methoxy-N-(3-methoxybenzyl)-5,6,7,8-tetrahydroquinoline-8-carboxamide

Step 1. (4-Isopropylphenyl)(3-methoxybenzyl)amine

Following the procedure described in Example 1 A, step 1,3-methoxybenzaldehyde and 4-isopropylaniline gave the title compound asa pale yellow oil.

¹H NMR (acetone-d₆) δ 7.24 (1H, t), 7.00-6.97 (4H, m), 6.81 (1H, dd),6.60 (2H, d), 5.29 (1H, br s), 4.32 (2H, d), 3.78 (3H, s), 2.80-2.73(1H, m), 1.17 (6H, d).

Step 2.(+/−)-N-(4-Isopropylphenyl)-2-methoxy-N-(3-methoxybenzyl)-5,6,7,8-tetrahydroquinoline-8-carboxamide

Following the procedure described in Example 1 A, step 3, using2-methoxy-5,6,7,8-tetrahydroquinoline, and(4-isopropylphenyl)(3-methoxybenzyl)amine gave the title compound as acolorless oil.

¹H NMR (acetone-d₆) δ 7.41 (2H, m), 7.34 (1H, d), 7.30 (2H, m), 7.20(1H, t), 6.92 (2H, m), 6.81 (1H, dd), 6.54 (1H, d), 5.28 (1H, d), 4.64(1H, d), 3.91-3.88 (4H, m), 3.74 (3H, s), 2.95-2.90 (1H, sept),2.75-2.69 (1H, m), 2.62-2.57 (1H, m), 2.11-2.02 (2H, m), 1.98-1.94 (1H,m), 1.51-1.46 (1H, m), 1.23 (6H, d).

EXAMPLE 9(+/−)-N-(4-Isopropylphenyl)-2-methoxy-N-[4-(methylthio)benzyl]-5,6,7,8-tetrahydroquinoline-8-carboxamide

Step 1. (4-Isopropylphenyl)[4-(methylthio)benzyl]amine

Following the procedure described in Example 1 A, step 1,4-(methylthio)benzaldehyde and 4-isopropylaniline gave the titlecompound as an off-white solid.

¹H NMR (acetone-d₆) δ 7.35 (2H, d), 7.25 (2H, d), 6.95 (2H, d), 6.60(2H, d), 5.25 (1H, br s), 4.30 (2H, d), 2.85 (1H, m), 2.50 (3H, s), 1.17(6H, d).

Step 2.(+/−)-N-(4-Isopropylphenyl)-2-methoxy-N-[4-(methylthio)benzyl]-5,6,7,8-tetrahydroquinoline-8-carboxamide

Following the procedure described in Example 1 A, step 3, using2-methoxy-5,6,7,8-tetrahydroquinoline, and(4-isopropylphenyl)[4-(methylthio)benzyl]amine gave the title compoundas an off-white solid

¹H NMR (acetone-d₆) δ 7.50 (9H, m), 6.60 (1H, d), 5.30 (1H, d), 4.60(1H, d), 3.90 (3H, s), 3.85 (1H, m), 3.00-1.50 (7H, m), 2.50 (3H, s),1.20 (6H, d).

EXAMPLE 10(+/−)-N-(4-Isopropylphenyl)-2-methoxy-N-[4-(methylsulfonyl)benzyl]-5,6,7,8-tetrahydroquinoline-8-carboxamide

To a 0.023 M solution of(+/−)-N-(4-isopropylphenyl)-2-methoxy-N-[4-(methylthio)benzyl]-5,6,7,8-tetrahydroquinoline-8-carboxamidein MeOH was added 3.1 equiv of Na₂WO₄.2H₂O and 6.3 equiv. of H₂O₂ 30%.After a period of 1 h at room temperature, the reaction mixture waspartitioned between EtOAc and aqueous saturated NaHCO₃. The organicphase was separated, washed with aqueous Na₂S₂O₃, dried over anhydrousNa₂SO₄, filtered and concentrated. The crude material was furtherpurified by flash chromatography, eluting with 100% EtOAc to provide thetitle compound as a yellow compound.

¹H NMR (acetone-d₆) δ 7.50 (9H, m), 6.60 (1H, d), 5.30 (1H, d), 4.60(1H, d), 3.90 (1H, m), 3.85 (3H, s), 3.00-1.50 (7H, m), 2.50 (3H, s),1.20 (6H, d).

EXAMPLE 11(+/−)-N-[4-(Difluoromethoxy)benzyl]-N-(4-isopropylphenyl)-2-methoxy-5,6,7,8-tetrahydroquinoline-8-carboxamide

Step 1. N-[4-(Difluoromethoxy)benzyl]-4-isopropylaniline

Following the procedure described in Example 1 A, step 1,4-(difluoromethoxy)benzaldehyde and 4-isopropylaniline gave the titlecompound as a pale yellow oil.

¹H NMR (acetone-d₆) δ 7.46 (2H, d), 7.14 (2H, d), 6.98 (2H, d), 6.97(1H, t), 6.59 (2H, d), 5.36 (1H, br s), 4.35 (2H, d), 2.79-2.73 (1H, m),1.17 (6H, d).

Step 2.(+/−)-N-[4-(Difluoromethoxy)benzyl]-N-(4-isopropylphenyl)-2-methoxy-5,6,7,8-tetrahydroquinoline-8-carboxamide

Following the procedure described in Example 1 A, step 3, using2-methoxy-5,6,7,8-tetrahydroquinoline, andN-[4-(difluoromethoxy)benzyl]-4-isopropylaniline gave the title compoundas a white solid.

¹H NMR (acetone-d₆) δ 7.41-7.39 (4H, m), 7.35-7.30 (3H, m), 7.11 (2H,d), 6.99 (1H, t), 6.55 (1H, d), 5.33 (1H, d), 4.62 (1H, d), 3.89-3.88(4H, m), 2.93 (1H, sept), 2.75-2.69 (1H, m), 2.62-2.57 (1H, m),2.10-2.02 (2H, m), 1.99-1.95 (1H, m), 1.49-1.45 (1H, m), 1.23 (6H, d).

EXAMPLE 12(+/−)-N-(4-Isopropylphenyl)-2-methoxy-N-[4-(trifluoromethoxy)benzyl]-5,6,7,8-tetrahydroquinoline-8-carboxamide

Step 1. (4-Isopropylphenyl)[4-(trifluoromethoxy)benzyl]amine

Following the procedure described in Example 1 A, step 1,4-(trifluoromethoxy)benzaldehyde and 4-isopropylaniline gave the titlecompound as a colorless oil.

¹H NMR (acetone-d₆) δ 7.54 (2H, d), 7.30 (2H, d), 6.99 (2H, d), 6.60(2H, d), 5.42 (1H, br s), 4.40 (2H, d), 2.79-2.73 (1H, m), 1.17 (6H, d).

Step 2.(+/−)-N-(4-Isopropylphenyl)-2-methoxy-N-[4-(trifluoromethoxy)benzyl]-5,6,7,8-tetrahydroquinoline-8-carboxamide

Following the procedure described in Example 1 A, step 3, using2-methoxy-5,6,7,8-tetrahydroquinoline, and(4-isopropylphenyl)[4-(trifluoromethoxy)benzyl]amine gave the titlecompound as a colorless oil.

¹H NMR (acetone-d₆) δ 7.48 (2H, d), 7.42-7.41 (2H, m), 7.35-7.31 (3H,m), 7.27 (2H, d), 6.55 (1H, d), 5.37 (1H, d), 4.65 (1H, d), 3.90-3.86(4H, m), 2.93 (1H, sept), 2.75-2.69 (1H, m), 2.62-2.57 (1H, m),2.10-1.96 (3H, m), 1.49-1.46 (1H, m), 1.23 (6H, d).

EXAMPLE 13(+/−)-N-(4-Isopropoxybenzyl)-N-(4-isopropylphenyl)-2-methoxy-5,6,7,8-tetrahydroquinoline-8-carboxamide

Step 1. N-(4-Isopropoxybenzyl)-4-isopropylaniline

Following the procedure described in Example 1 A, step 1,4-isopropoxybenzaldehyde and 4-isopropylaniline gave the title compoundas an off-white solid.

¹H NMR (acetone-d₆) δ 7.30 (2H, d), 6.98 (2H, d), 6.87 (2H, d), 6.61(2H, d), 5.15 (1H, br s), 4.60 (1H, sept), 4.24 (2H, d), 2.79-2.73 (1H,m), 1.30 (6H, d), 1.17 (6H, d).

Step 2.(+/−)-N-(4-Isopropoxybenzyl)-N-(4-isopropylphenyl)-2-methoxy-5,6,7,8-tetrahydroquinoline-8-carboxamide

Following the procedure described in Example 1 A, step 3, using2-methoxy-5,6,7,8-tetrahydroquinoline, andN-(4-isopropoxybenzyl)-4-isopropylaniline gave the title compound as afoam.

¹H NMR (acetone-d₆) δ 7.37-7.33 (3H, m), 7.29 (2H, d), 7.22 (2H, d),6.82 (2H, d), 6.54 (1H, d), 5.26 (1H, d), 4.62-4.57 (1H, m), 4.53 (1H,d), 3.87-3.83 (4H, m), 2.95-2.90 (1H, m), 2.75-2.69 (1H, m), 2.62-2.57(1H, m), 2.10-2.04 (2H, m), 1.97-1.94 (1H, m), 1.49-1.46 (1H, m), 1.30(6H, d), 1.23 (6H, d).

EXAMPLE 14(+/−)-N-[4-(Dimethylamino)benzyl]-N-(4-isopropylphenyl)-2-methyl-5,6,7,8-tetrahydroquinoline-8-carboxamide

Following the procedure described in Example 1 A, step 3, using2-methyl-5,6,7,8-tetrahydroquinoline, andN-[4-(dimethylamino)benzyl]-4-isopropylaniline gave the title compoundas a white solid.

¹H NMR (acetone-d₆) δ 7.39 (2H, m), 7.31 (1H, d), 7.25-7.23 (4H, m),6.99 (1H, d), 6.70 (2H, d), 5.22 (1H, d), 4.53 (1H, d), 3.90-3.87 (1H,m), 2.92-2.88 (7H, m), 2.80-2.74 (1H, m), 2.68-2.63 (1H, m), 2.52 (3H,s), 2.11-1.94 (3H, m), 1.50-1.47 (1H, m), 1.22 (6H, d).

EXAMPLE 15(+/−)-N-[4-(Dimethylamino)benzyl]-2-isopropyl-N-(4-isopropylphenyl)-5,6,7,8-tetrahydroquinoline-8-carboxamide

Step 1. 2-Ethylquinoline

To a 0.40 M solution of diisopropyl amine in THF at −10° C. was addedslowly 1.0 equiv of a solution of n-BuLi (2.5 M/hexane). After 10 min,the mixture was cooled to −78° C. and 0.9 equiv of quinaldine was addeddropwise. The red/orange solution was then stirred at 0° C. for 1 h. MeIwas then added and the reaction was stirred at room temperature for 2 h.The reaction was quenched with aqueous NH₄Cl solution, and thenextracted with EtOAc. The organic phase was washed with H₂O and brine.The solution was then dried (MgSO₄), filtered, and evaporated. The crudematerial was purified by flash chromatography with 1:10 EtOAc:hexanes togive the title compound as a pale yellow oil.

¹H NMR (acetone-d₆) δ 8.20 (1H, d), 7.95 (1H, d), 7.85 (1H, d), 7.70(1H, t), 7.50 (1H, t), 7.40 (1H, d), 2.95 (2H, q), 1.35 (3H, t).

Step 2. 2-Isopropylquinoline

Following the procedure described in Example 15, step 1,2-ethylquinoline and MeI gave the title compound as a tan colored oil.

¹H NMR (acetone-d₆) δ 8.25 (1H, d), 8.00 (1H, d), 7.90 (1H, d), 7.70(1H, t), 7.55 (1H, t), 7.45 (1H, d), 3.25 (1H, sept), 1.40 (6H, d).

Step 3. 2-Isopropyl-5,6,7,8-tetrahydroquinoline

To a 0.23 M solution of 2-isopropylquinoline in trifluoroacetic acid ina Parr flask was added 0.1 equiv of PtO₂. The suspension was set up onthe Parr apparatus at 44 psi H₂ overnight. After removal of the H₂,CH₂Cl₂ was added, and the suspension was filtered through Celite. Thesolvent was removed under vacuum, and the residue was partitionedbetween EtOAc and saturated NaHCO₃ solution. The organic layer waswashed with H₂O and brine, and was then dried over anhydrous MgSO₄,filtered and evaporated to give the title compound as a tan colored oil.

¹H NMR (acetone-d₆) δ 7.35 (1H, d), 6.95 (1H, d), 3.00-2.90 (1H, m),2.80 (2H, m), 2.70 (2H, m), 1.90 (2H, m), 1.80 (2H, m), 1.25 (6H, m).

Step 4.(+/−)-N-[4-(Dimethylamino)benzyl]-2-isopropyl-N-(4-isopropylphenyl)-5,6,7,8-tetrahydroquinoline-8-carboxamide

Following the procedure described in Example 1 A, step 3, using2-isopropyl-5,6,7,8-tetrahydroquinoline, andN-(4-dimethylaminobenzyl)-4-isopropylaniline gave the title compound asa foam.

¹H NMR (acetone-d₆) δ 7.49-7.40 (2H, m), 7.33 (1H, d), 7.28-7.19 (4H,m), 7.01 (1H, d), 6.70-6.63 (2H, m), 5.30 (1H, d), 4.46 (1H, d),3.94-3.89 (1H, m), 3.09-3.02 (1H, m), 2.95-2.87 (7H, m), 2.82-2.74 (1H,m), 2.68-2.62 (1H, m), 2.16-2.01 (2H, m), 2.00-1.92 (1H, m), 1.51-1.44(1H, m), 1.33 (6H, d), 1.22 (6H, d).

EXAMPLE 16(+/−)-N-[4-(Dimethylamino)benzyl]-2-ethoxy-N-(4-isopropylphenyl)-5,6,7,8-tetrahydroquinoline-8-carboxamide

Step 1. 2-Ethoxy-5,6,7,8-tetrahydroquinoline

Following the procedure described in Example 1 A, step2,5,6,7,8-tetrahydroquinolin-2(1H)-one and EtI gave the title compoundas a pale yellow oil.

¹H NMR (acetone-d₆) δ 7.42 (1H, d), 6.58 (1H, d), 4.39 (2H, q),2.85-2.82 (2H, m), 2.78-2.76 (2H, m), 1.97-1.93 (2H, m), 1.90-1.86 (2H,m), 1.43 (3H, t).

Step 2.(+/−)-N-[4-(Dimethylamino)benzyl]-2-ethoxy-N-(4-isopropylphenyl)-5,6,7,8-tetrahydroquinoline-8-carboxamide

Following the procedure described in Example 1 A, step 3, using2-ethoxy-5,6,7,8-tetrahydroquinoline, andN-(4-dimethylaminobenzyl)-4-isopropylaniline gave the title compound asa waxy oil.

¹H NMR (acetone-d₆) δ 7.34-7.24 (5H, m), 7.14 (2H, d), 6.65 (2H, d),6.50 (1H, d), 5.22 (1H, d), 4.48 (1H, d), 4.37-4.26 (2H, m), 3.83-3.80(1H, m), 2.94-2.86 (7H, m), 2.73-2.67 (1H, m), 2.59-2.54 (1H, m),2.10-1.92 (3H, m), 1.47-1.40 (1H, m), 1.36 (3H, t), 1.23 (6H, d).

EXAMPLE 17(+/−)-N-[4-(Dimethylamino)benzyl]-2-isopropoxy-N-(4-isopropylphenyl)-5,6,7,8-tetrahydroquinoline-8-carboxamide

Step 1. 2-Isopropoxy-5,6,7,8-tetrahydroquinoline

Following the procedure described in Example 1 A, step2,5,6,7,8-tetrahydroquinolin-2(1H)-one and i-PrI gave the title compoundas a pale yellow oil.

¹H NMR (acetone-d₆) δ 7.26 (1H, d), 6.39 (1H, d), 5.27-5.24 (1H, m),2.69-2.68 (2H, m), 2.64-2.61 (2H, d), 1.81-1.74 (4H, m), 1.25 (6H, d).

Step 2.(+/−)-N-[4-(Dimethylamino)benzyl]-2-isopropoxy-N-(4-isopropylphenyl)-5,6,7,8-tetrahydroquinoline-8-carboxamide

Following the procedure described in Example 1 A, step 3, using2-isopropoxy-5,6,7,8-tetrahydroquinoline, andN-(4-dimethylaminobenzyl)-4-isopropylaniline gave the title compound asa yellow oil.

¹H NMR (acetone-d₆) δ 7.31-7.25 (5H, m), 7.13 (2H, d), 6.66 (2H, d),6.46 (1H, d), 5.30 (1H, sept), 5.14 (1H, d), 4.56 (1H, d), 3.82-3.80(1H, m), 2.95-2.89 (7H, m), 2.73-2.67 (1H, m), 2.59-2.54 (1H, m),2.08-2.00 (2H, m), 1.96-1.92 (1H, m), 1.48-1.40 (1H, m), 1.37 (3H, d),1.31 (3H, d), 1.23 (6H, d).

EXAMPLE 18(+/−)-N-[4-(Dimethylamino)benzyl]-N-(4-isopropylphenyl)-2-(methylthio)-5,6,7,8-tetrahydroquinoline-8-carboxamide

Step 1. 2-(Methylthio)-5,6,7,8-tetrahydroquinoline

To a 0.20 M solution of 2-chloro-5,6,7,8-tetrahydroquinoline in NMP wasadded 1.5 equiv of NaSMe. After a period of 15 min at 100° C., thereaction mixture was partitioned between EtOAc and H₂O. The organiclayer was separated, dried over anhydrous Na₂SO₄, filtered andconcentrated. The crude material was further purified by flashchromatography eluting with 10% EtOAc in hexanes to provide the titlecompound as a yellow compound.

¹H NMR (acetone-d₆) δ 7.25 (1H, d), 6.95 (1H, d), 2.85 (2H, m), 2.70(2H, m), 2.50 (3H, s), 1.85 (2H, m), 1.75 (2H, m).

Step 2.(+/−)-N-[4-(Dimethylamino)benzyl]-N-(4-isopropylphenyl)-2-(methylthio)-5,6,7,8-tetrahydroquinoline-8-carboxamide

Following the procedure described in Example 1 A, step 3, using2-(methylthio)-5,6,7,8-tetrahydroquinoline, andN-(4-dimethylaminobenzyl)-4-isopropylaniline gave the title compound asa yellow compound.

¹H NMR (acetone-d₆) δ 7.30 (5H, m), 7.15 (2H, d), 7.00 (1H, d), 6.80(2H, d), 5.10 (1H, d), 4.50 (1H, d), 3.85 (1H, m), 2.90 (6H, s),3.00-1.50 (7H, m) 2.50 (3H, s), 1.20 (6H, d).

1.-26. (canceled)
 27. A compound of Formula I

or a pharmaceutically acceptable salts thereof; k is 0, 1, 2 or 3; R²and R³ are each hydrogen; R¹ is selected from the group consisting of(1) hydrogen, (2) —C₁₋₆alkyl, (3) —OC₁₋₆alkyl, (4) —SC₁₋₆alkyl, (5)—C₂₋₆alkenyl, (6) —C₃₋₆cycloalkyl, (7) aryl, (8) heteroaryl, (9)heterocyclic, (10) —C₁₋₆alkylaryl, (11) —C₁₋₆alkylheteroaryl (12)—C₁₋₆alkylheterocyclic, (13) —O-aryl, (14) —O-heteroaryl, (15)—O-heterocyclic, (16) —OC₁₋₆alkylaryl, (17) —OC₁₋₆alkylheteroaryl (18)—OC₁₋₆alkylheterocyclic, (19) halo, (20) —CN, (21) —NO₂, (22)—C(O)—C₁₋₆alkyl, (23) —C(O)-aryl, (24) —C(O)-heteroaryl, (25)—C(O)-heterocyclic, (26) —C(O)—C₁₋₆alkyl, (27) —NH—C₁₋₆alkyl, (28)—N(C₁₋₆alkyl)(C₁₋₆alkyl) (29) —C(O)—NH₂, (30) —C(O)—NH—C₁₋₆alkyl, (31)—C(O)—N(C₁₋₆alkyl)(C₁₋₆alkyl), and (32) S(O)n-C₁₋₆alkyl, whereindefinitions (1) to (18) and (22) to (32) are optionally substituted with1, 2 or 3 substituents selected from the group consisting of halo,hydroxyl, —CN, —NO₂, NH₂, R⁴ and R⁵ are each independently selected fromthe group consisting of (1) hydrogen, (2) —C₁₋₆alkyl, (3) —OC₁₋₆alkyl,(4) —SC₁₋₆alkyl, (5) —C₂₋₆alkenyl, (6) —C₃₋₆cycloalkyl, (7) aryl, (8)heteroaryl, (9) heterocyclic, (10) —C₁₋₆alkylaryl, (11)—C₁₋₆alkylheteroaryl (12) —C₁₋₆alkylheterocyclic, (13) —O-aryl, (14)—O-heteroaryl, (15) —O-heterocyclic, (16) —OC₁₋₆alkylaryl, (17)—OC₁₋₆alkylheteroaryl, (18) —OC₁₋₆alkylheterocyclic, (19) halo, (20)—CN, (21) —NO₂, (22) —C(O)—C₁₋₆alkyl, (23) —C(O)-aryl, (24)—C(O)-heteroaryl, (25) —C(O)-heterocyclic, (26) —C(O)—C₁₋₆alkyl, (27)NH₂, (28) —NH—C₁₋₆alkyl, (29) —N(C₁₋₆alkyl)(C₁₋₆alkyl) (30) —C(O)—NH₂,(31) —C(O)—NH—C₁₋₆alkyl, (32) —C(O)—N(C₁₋₆alkyl)(C₁₋₆alkyl), (33) —SH,and (34) S(O)n-C₁₋₆alkyl, wherein n is 1 or 2; wherein definitions (1)to (18) and (22) to (32) and (34) are optionally substituted with 1, 2or 3 substituents selected from the group consisting of halo, hydroxyl,—CN, —NO₂, NH₂; R⁶ is hydrogen or C₁₋₃alkyl, optionally substituted with1, 2 or 3 substituents selected from R⁶ is hydrogen or C₁₋₃alkyl,optionally substituted with 1, 2 or 3 substituents selected from (1)-halo, (2) —NR⁷R⁸, (3) aryl, (4) —OC₁₋₃alkyl, (5) —SC₁₋₃alkyl, and (6)—S(O)₂C₁₋₃alkyl, (7) hydroxyl; each R⁷ and each R⁸ are eachindependently hydrogen or C₁₋₃alkyl, optionally substituted with 1, 2 or3 substituents selected from (1) -halo, (2) C₁₋₃alkyl, (3) —OC₁₋₆alkyl,(4) —SC₁₋₆alkyl, (5) —S(O)₂C₁₋₆alkyl, Ar is aryl or heteroaryl,optionally substituted with 1, 2 or 3 substitutents selected from (1)-halo, (2) C₁₋₆alkyl, optionally substituted with 1, 2, 3 or 4 halogroups, (3) —NR⁷R⁸, (4) aryl, (5) —OC₁₋₆alkyl, optionally substitutedwith 1, 2, 3 or 4 halo groups, (6) —SC₁₋₆alkyl, (7) —S(O)₂C₁₋₆alkyl; Ar₁is aryl or heteroaryl or C₃₋₆cycloalkyl, optionally substituted with 1,2 or 3 substitutents selected from (1) -halo, (2) C₁₋₆alkyl, optionallysubstituted with 1, 2, 3 or 4 halo groups, (3) —NR⁷R⁸, (4) aryl, (5)—OC₁₋₆alkyl, optionally substituted with 1, 2, 3 or 4 halo groups, (6)—SC₁₋₆alkyl, and (7) —S(O)₂C₁₋₆alkyl.
 28. A compound of claim 27wherein: R¹ is selected from the group consisting of (1) —C₁₋₆alkyl, (2)—OC₁₋₆alkyl, (3) —SC₁₋₆alkyl, (4) —C₂₋₆alkenyl, and (5) —C₃₋₆cycloalkyl;wherein definitions (1) to (5) are optionally substituted with 1, 2 or 3substituents selected from the group consisting of halo, hydroxyl, —CN,—NO₂, and NH₂.
 29. A compound according to claim 27 wherein: R⁴ and R⁵are each hydrogen.
 30. A compound according to claim 27 wherein: k is 1.31. A compound according to claim 27 wherein Ar and Ar₁ are eachindependently an optionally substituted phenyl or pyridyl.
 32. Acompound according to claim 27 wherein: R¹ is selected from the groupconsisting of (1) —C₁₋₃alkyl, (2) —OC₁₋₃alkyl, (3) —SC₁₋₃alkyl, (4)—C₂₋₄alkenyl, and (5) —C₃₋₆cycloalkyl; wherein definitions (1) to (5)are optionally substituted with 1, 2 or 3 substituents selected from thegroup consisting of halo, hydroxyl, —CN, —NO₂, and NH₂.
 33. A compoundaccording to claim 27 wherein: Ar and Ar₁ are each optionallysubstituted with 1, 2 or 3 substituents selected from (1) -halo, (2)C₁₋₄alkyl, optionally substituted with 1, 2, 3 or 4 halo groups, (3)—NR⁷R⁸, (4) phenyl, (5) —OC₁₋₄alkyl, optionally substituted with 1, 2, 3or 4 halo groups, (6) —SC₁₋₄alkyl; and R⁷ and R⁸ are each independentlyhydrogen or methyl.
 34. A pharmaceutical composition comprising acompound according to claim 27 or a pharmaceutically acceptable saltthereof; and a pharmaceutically acceptable carrier.
 35. A Method oftreatment or prevention of a C5a mediated disease or disorder comprisingadministering to a subject in need of such treatment or prevention, atherapeutically effective amount of a compound according to claim 1 or apharmaceutically acceptable salt.
 36. A Method of antagonizing C5a in asubject, comprising administering to a subject in need of suchantagonism, a therapeutically effective amount of a compound accordingto claim 27 or a pharmaceutically acceptable salt.
 37. A methodaccording to claim 27, wherein the disease or disorder is rheumatoidarthritis, systemic lupus erythematosus, glomerulonephritis, ischemicheart diseases, reperfusion injury, sepsis, psoriasis, atherosclerosis,inflammatory bowel diseases, adult respiratory distress syndrome,asthma, COPD and Alzheimer's disease.